Magnoflorine alleviates depression-like behaviors via modulation of serotonergic signaling and neurotrophic pathways

Magnoflorine alleviates depression-like behaviors in a chronic stress model • Magnoflorine modulates serotonergic signaling involving 5-HT 1A receptor and SERT • Neuroprotective effects are associated with regulation of BDNF and ERK pathways • Magnoflorine restores monoamine neurotransmitter levels and neuroplasticity • Findings suggest potential therapeutic relevance for depression treatment Depression is a prevalent and debilitating psychiatric disorder characterized by dysregulation of monoaminergic neurotransmission and impaired neuroplasticity, and current antidepressants are limited by delayed onset and suboptimal efficacy, necessitating novel multi-target therapeutics. Magnoflorine, an alkaloid derived from Ziziphi Spinosae Semen (Suanzaoren), has been reported to possess antianxiety and neuroprotective activities, but its antidepressant effects and underlying mechanisms remain unclear. This study employed an integrated strategy combining network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation to investigate the antidepressant effects of magnoflorine. The effects of magnoflorine were evaluated in corticosterone (CORT)-induced HT-22 cells and a chronic unpredictable mild stress (CUMS) mouse model using behavioral tests, neurochemical analysis, histological analysis, and Western blotting. Network pharmacology analysis suggested that magnoflorine may regulate multiple targets involved in depression, particularly serotonergic signaling pathways. Molecular docking and molecular dynamics simulations suggested potential interactions between magnoflorine and 5-HT 1A R/SERT. In vitro and in vivo experiments demonstrated that magnoflorine ameliorated CORT-induced neuronal injury and CUMS-associated depression-like behaviors, restored hippocampal monoamine levels, and alleviated neuronal damage. These effects were accompanied by alterations in 5-HT 1A R and SERT expression and enhanced ERK phosphorylation and BDNF expression. Collectively, these findings suggest that the antidepressant-like effects of magnoflorine are associated with modulation of serotonergic and neurotrophic signaling. Download: Download high-res image (261KB) Download: Download full-size image